Plasma biomarkers for Alzheimer's disease in middle-aged and older Japanese men: A population-based cross-sectional...

BackgroundThe diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) neuropathology has been demonstrated in individuals with cognitive impairment; however, evidence for reliable preclinical stage diagnostic methods remains insufficient.ObjectiveTo identify confounding variables that may obscure the interpretation of these biomarkers, we examined their associations with various physiological indices including age, renal function, and cognitive function in Japanese men from the general population.MethodsPlasma were collected from 845 randomly selected Japanese men participants (aged >40 years) to measure 40- and 42-amino acid amyloid-β (Aβ₄₀ and Aβ₄₂), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and neurofilament light chain (NfL) using an automated immunoassay system. Cognitive function was assessed using the Cognitive Abilities Screening Instrument (CASI). Linear regression models were constructed to estimate association strengths with correction for possible confounding variables.ResultsPlasma Aβ₄₀, Aβ₄₂, T-tau, P-tau181, NfL, and P-tau181/T-tau increased with age and declining glomerular filtration rate (eGFR), whereas Aβ₄₂/Aβ₄₀ decreased with age. Higher T-tau and P-tau181 were associated with lower CASI scores after adjusting for age and eGFR. Individuals in older age groups with Aβ₄₂/Aβ₄₀ ratios less than or equal to a cutoff ("amyloid-positive") also exhibited higher P-tau181, NfL, and P-tau181/T-tau than amyloid-negative individuals, with no significant difference in mean CASI score.ConclusionsOur results confirm that plasma AD biomarkers are significantly influenced by age and renal clearance rate. Notably, higher T-tau and P-tau181 were associated with preclinical cognitive impairment. Additionally, a lower Aβ₄₂/Aβ₄₀ was associated with asymptomatic tau pathology and neurodegeneration.